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CCR5 antagonism as a potential therapeutic approach for cardiac fibrosis
Author(s) -
Liang Wenjing,
Gorr Matthew W.,
Insel Paul A.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.839.2
Subject(s) - maraviroc , cardiac fibrosis , ccr5 receptor antagonist , fibrosis , cardiac function curve , receptor , pharmacology , agonist , myofibroblast , fibroblast , chemokine receptor , medicine , biology , chemokine , immunology , cancer research , heart failure , in vitro , biochemistry , human immunodeficiency virus (hiv)
Fibrosis of the heart occurs in multiple cardiac disorders and is associated with significant morbidity and mortality. Effective therapy to treat and prevent this pathological process remains a major clinical challenge. G protein‐coupled receptors (GPCRs) play a vital role in altering the function of cardiac cells and are thus major therapeutic targets for cardiovascular disorders. We tested the hypothesis that the chemokine receptor CCR5, which is a co‐receptor for HIV infection of immune cells, may contribute to and thus be a novel therapeutic target in cardiac fibrosis. We found prominent CCR5 expression in cardiac fibroblasts isolated from mice and rats. Expression of CCR5 was significantly increased when fibroblasts were treated with hypoxia to induce a myofibroblast phenotype. Cardiac fibroblasts exposed 72 hours to hypoxia increased CCR5 expression 5.8±1.7‐fold compared to normoxia (p=0.0327) in cells isolated from mice, and 4.2±1.1‐fold in cells isolated from rat (p=0.0178). To assess the role for CCR5 in experimental cardiac fibrosis, we used pharmacological CCR5 activation and inactivation in mouse and rat cardiac fibroblasts. Maraviroc, an FDA‐approved antagonist of CCR5 reduced the expression of fibrotic markers, including α‐smooth muscle actin and collagens I and III in mouse and rat cardiac fibroblasts grown under both normoxic and hypoxic conditions. Treatment with recombinant CCL4, the agonist of CCR5, increased these fibrotic markers in rat cardiac fibroblasts. In addition, Maraviroc reduced cardiac fibroblast proliferation and migration while CCL4 had the opposite effect. We conclude that the CCL4‐CCR5 pathway can regulate activity of cardiac fibroblasts and may be a therapeutic target for cardiac fibrosis. Support or Funding Information Supported by R21AG52914 and T32HL007444‐34 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .